tbuckley/cabot-search huggingface dataset:
3D genome organization in the epithelial-mesenchymal transition spectrum
Authors: Qing You Pang, Tuan Zea Tan, Vignesh Sundararajan, Yi-Chia Chiu, Edward Yu Wing Chee, Vin Yee Chung, Mahesh A. Choolani, Ruby Yun-Ju Huang
Journal: Genome biology (2022)

Abstract Background The plasticity along the epithelial-mesenchymal transition (EMT) spectrum has been shown to be regulated by various epigenetic repertoires. Emerging evidence of local chromatin conformation changes suggests that regulation of EMT may occur at a higher order of three-dimensional genome level. Results We perform Hi-C analysis and combine ChIP-seq data across cancer cell lines representing different EMT states. We demonstrate that the epithelial and mesenchymal genes are regulated distinctively. We find that EMT genes are regulated within their topologically associated domains (TADs), with only a subset of mesenchymal genes being influenced by A/B compartment switches, indicating topological remodeling is required in the transcriptional regulation of these genes. At the TAD level, epithelial and mesenchymal genes are associated with different regulatory trajectories. The epithelial gene-residing TADs are enriched with H3K27me3 marks in the mesenchymal-like states. The mesenchymal gene-residing TADs, which do not show enrichment of H3K27me3 in epithelial-like states, exhibit increased interaction frequencies with regulatory elements in the mesenchymal-like states. Conclusions We propose a novel workflow coupling immunofluorescence and dielectrophoresis to unravel EMT heterogeneity at single-cell resolution. The predicted three-dimensional structures of chromosome 10, harboring Vimentin, identify cell clusters of different states. Our results pioneer a novel avenue to decipher the complexities underlying the regulation of EMT and may infer the barriers of plasticity in the 3D genome context.
Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma
Authors: Petros Grivas, Evgeny Kopyltsov, Po-Jung Su, Francis X. Parnis, Se Hoon Park, Yoshiaki Yamamoto, Peter C. Fong, Christophe Tournigand, Miguel A. Climent Duran, Aristotelis Bamias, Claudia Caserta, Jane Chang, Paul Cislo, Alessandra di Pietro, Jing Wang, Thomas Powles
Journal: European Urology (2022)

In JAVELIN Bladder 100, avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) versus BSC alone in patients with advanced urothelial carcinoma (aUC) without disease progression with first-line platinum-containing chemotherapy.To evaluate patient-reported outcomes (PROs) with avelumab plus BSC versus BSC alone.A randomized phase 3 trial (NCT02603432) was conducted in 700 patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line gemcitabine plus cisplatin or carboplatin. PROs were a secondary endpoint.Avelumab plus BSC (n = 350) or BSC alone (n = 350).National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol five-level EQ-5D (EQ-5D-5L) assessments were analyzed using descriptive statistics and mixed-effect models. Time to deterioration (TTD; prespecified definition: a ≥3-point decrease from baseline in the FBlSI-18 disease-related symptoms-physical subscale for two consecutive assessments) was evaluated via Kaplan-Meier analyses.Completion rates for scheduled on-treatment PRO assessments were >90% (overall and average per assessment). Results from descriptive analyses and mixed-effect or repeated-measures models of FBlSI-18 and EQ-5D-5L were similar between arms. TTD was also similar, both in the prespecified analysis (hazard ratio 1.26 [95% confidence interval: 0.90, 1.77]) and in the post hoc analyses including off-treatment assessments and different event definitions. Limitations included the open-label design and limited numbers of evaluable patients at later time points.Addition of avelumab first-line maintenance to BSC in patients with aUC that had not progressed with first-line platinum-containing chemotherapy prolonged OS, with a relatively minimal effect on quality of life.In this trial of people with advanced urothelial carcinoma who had benefited from first-line chemotherapy (ie, had stable disease or reduced tumor size), treatment with avelumab maintenance plus best supportive care (BSC) versus BSC alone improved survival significantly, without compromising quality of life, as reported by the patients themselves.
Collaborative Co-Managed Care (C3): A Sustainable Gastrointestinal Motility Practice Model
Authors: Eric D. Shah, Lauren A. Barry, Mariah L. Connolly, Kathy A. Del Giudice, Richard T. Dillehay, Carol Greeley, Shari McBride, Kayla A. Northam, Elizabeth A. Pelletier, Jessica A. Perrone, Richard I. Rothstein, Jamie D. Sanchez, Corey A. Siegel, Emily E. Sieglinger, Patrick N. Tetreault, Joseph D. Weiss, Tammy-Lynn A. Wilson, Michael A. Curley
Journal: Clinical Gastroenterology and Hepatology (2022)
Trial in progress: A phase 1b study evaluating the safety, tolerability, and preliminary anti-tumor activity of NT-I7 (efineptakin alfa), a long-acting human IL-7, post-tisagenlecleucel in subjects with relapsed/refractory large B-cell lymphoma.
Authors: Armin Ghobadi, L Elizabeth Budde, Ahmed Galal, Kristina Stermer, TaShara Lynn Austin, Jean Fan, John F. DiPersio
Journal: Journal of Clinical Oncology (2022)

TPS7596 Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy with tisagenlecleucel (Kymriah) is standard of care (SOC) for patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). CAR-T expansion is a strong predictor of response to this therapy. NT-I7 (efineptakin alfa) is a first in-class, long-acting human IL-7 previously shown clinically in solid tumor studies to increase the number and functionality of T-cells in peripheral blood and within tumors. In a CD19 + lymphoma xenograft mouse model that received anti-CD19 universal CAR-T infusion, NT-I7 treatment prolonged survival and enhanced CAR-T gene expression of functional markers, proliferation, persistence, and tumor killing. We hypothesize that NT-I7 administration after tisagenlecleucel SOC for subjects with r/r LBCL may increase expansion and persistence of CAR-T, leading to increased tumor response rate and improved clinical outcomes without safety concerns. Methods: This phase 1b study consists of a dose-escalation phase followed by a dose expansion. In dose escalation, subjects receive tisagenlecleucel infusion on Day 0 and a single dose of NT-I7 on Day 21, at 7 dose levels (DLs 1-7): 60, 120, 240, 360, 480, 600, and 720 μg/kg. DLs 1 and 2 will enroll 1 subject each, followed by a 3+3 design for the remaining DLs. Up to 42 subjects will be enrolled for the dose-escalation phase and up to 15 subjects in the dose-expansion phase, treated at the recommended phase 2 dose (RP2D). Eligible subjects are ≥18 years of age with biopsy-proven diagnosis of r/r LBCL after ≥2 lines of systemic therapy, including diffuse LBCL (DLBCL) not otherwise specified (NOS), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Subjects must be eligible for tisagenlecleucel as SOC. Subjects who have received prior CD19-directed therapy are ineligible. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) and/or RP2D for NT-I7 with this regimen. Secondary objectives are to explore the anti-tumor activity of this regimen for r/r LBCL. The effect of NT-I7 after tisagenlecleucel infusion on the safety profile regarding Grade ≥3 Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) will also be evaluated. Exploratory objectives are to assess pharmacokinetic parameters of tisagenlecleucel with NT-I7 administration, and correlative studies will evaluate the effects of this regimen not limited only to the expansion of lymphocytes and serum cytokines. As of January 3, 2022, 2 subjects have received NT-I7 in the dose-escalation phase at DL1 and DL2. Clinical trial information: NCT05075603.
Bisphenol A exposures and hormone concentrations in a cohort of women receiving aromatase inhibitor therapy for breast cancer.
Authors: Kimberly Robien, Mark N. Kirstein, Pamala A. Pawloski, Alice C. Shapiro
Journal: Journal of Clinical Oncology (2022)

e12535 Background: Bisphenol A (BPA), a widely used chemical in plastics production, has been shown to have estrogenic activity, although it is unclear whether BPA exposure alters effectiveness of aromatase inhibitor (AI) treatment among women with breast cancer. In vitro studies have indicated that at higher concentrations (≥10 -4 μM), BPA inhibits aromatase expression and activity, whereas at environmentally relevant concentrations (≤10 -8 μM), BPA increases aromatase expression and activity. Few in vivo studies have investigated the association between BPA exposure and estrogen concentrations among non-pregnant women. This pilot study among post-menopausal women receiving AI therapy evaluated whether BPA is detectable in participants’ urine, and the association between BPA and hormone concentrations. Methods: This study was ancillary to a larger intervention study (ClinicalTrials.gov NCT01509079), and participants provided informed consent for this ancillary study under a protocol approved by the institutional review boards of Park Nicollet Institute/HealthPartners and the University of Minnesota. AI adherence during the 4 weeks prior to the baseline visit was monitored through weekly diaries. Participants were instructed to collect spot urine collections in sterile, BPA-free polypropylene containers in the 24 hours prior to the baseline study visit. Serum hormone concentrations were measured using serum collected at the baseline study visit. The Breast Cancer Prevention Trial - Musculoskeletal Symptom (BCPT-MS) scale was used to assess AI-associated musculoskeletal syndrome symptoms at the baseline study visit. Results: Fourteen women agreed to participate in the pilot study, however one participant’s data was excluded due to substances interfering with BPA measurement. BPA was detected in urine from all 13 remaining participants. Geometric mean urinary BPA concentration (1.55 mcg/g creatinine, 95% confidence interval (CI): 0.98-2.45) was higher than concentrations reported for females (1.36 mcg/g creatinine, 95% CI: 1.23-1.51) in the 2013-14 National Health and Nutrition Examination Survey biomonitoring data. Age, body mass index, and percent body fat did not differ between women above or below the study median urinary BPA concentrations (1.49 ng/mL). Women with BPA concentrations &gt;1.49 ng/mL had consistently lower serum estrone (5.0 vs. 7.0 pg/mL, p=0.15), estradiol (2.8 vs. 3.6 pg/mL, p=0.04), and testosterone (21.5 vs 23.8 ng/dL, p=0.28) concentrations compared to women with lower BPA concentrations. No statistically significant differences in BCPT-MS scores were observed between women with higher vs. lower urinary BPA concentrations. Conclusions: These preliminary findings suggest that BPA exposures may work in concert with AIs to lower serum estrogen levels. However, further research is needed to confirm these findings.
EPCT-01. Pediatric Brain Tumor Consortium (PBTC)-055: A phase I study of trametinib and hydroxychloroquine (HCQ) for BRAF-fusion or Neurofibromatosis type-1 (NF1)-associated pediatric gliomas
Authors: Lindsey M Hoffman, Jean Mulcahy Levy, Lindsay Kilburn, Catherine Billups, Vanetria Stokes, Emily McCourt, Tina Young Poussaint, Olivia Campagne, Sonia Partap, Kathleen Dorris, Sameer Farouk Sait, Giles Robinson, Patricia Baxter, Clinton F Stewart, Jason Fangusaro, Arzu Onar-Thomas, Ira Dunkel
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Autophagy is a highly conserved process by which intracellular components are degraded and recycled promoting cell survival. Preclinically, autophagy has been implicated as a resistance mechanism in BRAF-mutant glioma cells treated with MAPK-pathway inhibitors. HCQ, an oral autophagy inhibitor, has been evaluated preclinically and clinically to overcome resistance. METHODS: PBTC-055 (NCT04201457) is a phase I/II trial of HCQ combined with trametinib (BRAF-fusion or NF1-associated gliomas) or trametinib and dabrafenib (BRAFV600E gliomas) in patients &amp;lt; 30 years with progressive glioma. Prior treatment with RAF and/or MEK inhibitor with sub-optimal response (no response or response followed by progression on therapy) was required. Here, we present phase I data combining trametinib with HCQ utilizing a rolling-6 design. HCQ was administered at escalating dose levels (8, 15, or 20 mg/kg/day divided BID) in combination with standard pediatric trametinib dosing. All patients received prior MEK inhibitor therapy; 5/18 (28%) exhibited no response and 13/18 (72%) progressed on active therapy. RESULTS: Eighteen eligible/evaluable subjects were enrolled. Median age was 9.6 years (2.5-20.4 years); 10 were male. There were 2 dose-limiting toxicities (both grade 3 rash one each at DL1 and DL3). The highest dose level of HCQ (20 mg/kg/day divided BID) was declared the RP2D. Grade 3 adverse events possibly related to therapy included skin infection, rash, cardiac ejection fraction decrease, weight loss, and anorexia. There were no grade 4 or 5 attributable toxicities. Preliminarily, combination pharmacokinetic assessment revealed similar metabolism of trametinib to that reported as a single agent; HCQ demonstrated more rapid clearance compared to adults. Pharmacodynamic assessments are ongoing. CONCLUSIONS: The combination of trametinib and HCQ is safe with a RP2D of HCQ of 20 mg/kg/day divided BID. Currently, subjects are enrolling on the phase II portion evaluating the efficacy of this novel combination.
Efficacy of Epigallocatechin-3-Gallate in Preventing Dermatitis in Patients With Breast Cancer Receiving Postoperative Radiotherapy
Authors: Hanxi Zhao, Wanqi Zhu, Xianguang Zhao, Xiaolin Li, Zhengbo Zhou, Meizhu Zheng, Xiangjiao Meng, Lingling Kong, Shuyu Zhang, Dan He, Ligang Xing, Jinming Yu
Journal: JAMA Dermatology (2022)

Safe and effective prophylactic therapies for radiation-induced dermatitis (RID) remain an unmet need.To determine if epigallocatechin-3-gallate (EGCG) solution reduces the incidence of RID in patients undergoing radiotherapy after breast cancer surgery.This phase 2 double-blind, placebo-controlled randomized clinical trial enrolled 180 patients with breast cancer receiving postoperative radiotherapy at Shandong Cancer Hospital and Institute in Shandong, China, between November 2014 and June 2019. Data analysis was performed from September 2019 to January 2020.Participants were randomly assigned (2:1) to receive either EGCG solution (660 μmol/L) or placebo (0.9% NaCl saline) sprayed to the whole radiation field from day 1 of the radiation until 2 weeks after radiation completion.The primary end point was incidence of grade 2 or worse RID, defined by the Radiation Therapy Oncology Group scale. The secondary end points included RID index (RIDI), symptom index, changes in the skin temperature measured by infrared thermal images, and safety.A total of 180 eligible patients were enrolled, of whom 165 (EGCG, n = 111; placebo, n = 54) were evaluable for efficacy (median [range] age, 46 [26-67] years). The occurrence of grade 2 or worse RID was significantly lower (50.5%; 95% CI, 41.2%-59.8%) in the EGCG group than in the placebo group (72.2%; 95% CI, 60.3%-84.1%) (P = .008). The mean RIDI in the EGCG group was significantly lower than that in the placebo group. Furthermore, symptom indexes were significantly lower in patients receiving EGCG. Four patients (3.6%) had adverse events related to the EGCG treatment, including grade 1 pricking skin sensation (3 [2.7%]) and pruritus (1 [0.9%]).In this randomized clinical trial, prophylactic use of EGCG solution significantly reduced the incidence and severity of RID in patients receiving adjuvant radiotherapy for breast cancer. It has the potential to become a new choice of skin care for patients receiving radiotherapy.ClinicalTrials.gov Identifier: NCT02580279.
In Search of the Optimal Antithrombotic Regimen for Intracerebral Hemorrhage Survivors with Atrial Fibrillation
Authors: Teng J. Peng, Catherine Viscoli, Pooja Khatri, Stacey Q. Wolfe, Nirav R. Bhatt, Tarun Girotra, Hooman Kamel, Kevin N. Sheth
Journal: Drugs (2022)
Author Correction: Detecting visually significant cataract using retinal photograph-based deep learning
Authors: Yih-Chung Tham, Jocelyn Hui Lin Goh, Ayesha Anees, Xiaofeng Lei, Tyler Hyungtaek Rim, Miao-Li Chee, Ya Xing Wang, Jost B. Jonas, Sahil Thakur, Zhen Ling Teo, Ning Cheung, Haslina Hamzah, Gavin S. W. Tan, Rahat Husain, Charumathi Sabanayagam, Jie Jin Wang, Qingyu Chen, Zhiyong Lu, Tiarnan D. Keenan, Emily Y. Chew, Ava Grace Tan, Paul Mitchell, Rick S. M. Goh, Xinxing Xu, Yong Liu, Tien Yin Wong, Ching-Yu Cheng
Journal: Nature Aging (2022)
Does the primary tumor origin affect the prognosis of patients with gastrointestinal malignancies and peritoneal carcinomatosis?
Authors: Krista Michelle Wong, Kanchi Patell, Seshma Ramsawak, Hasan Abuamsha
Journal: Journal of Clinical Oncology (2022)

e16223 Background: Multiple gastrointestinal malignancies have the potential to metastasize in the peritoneal cavity. Peritoneal carcinomatosis (PC) is often associated with disease progression and poor prognosis. However, there has been limited data on the impact of tumor origin on the survival outcomes in patients with PC. We sought to examine the differences in the cancer-specific survival of gastrointestinal malignancies with PC. Methods: We performed a retrospective study of patients ≥18 years of age diagnosed with gastrointestinal malignancies (stomach, colorectal, small intestine, appendix) with PC between 2010-2016 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. The study endpoint was cancer-specific mortality (CSM). We used the Kaplan-Meier method to evaluate the cancer-specific survival for each primary tumor. Cox proportional hazard regression analysis was used to examine the association between CSM and other patient characteristics. The effects were expressed as hazard ratios (HR) and 95% confidence intervals (CI). Results: We identified 7374 patients who met the inclusion criteria; 2797 (37.9%) with stomach cancer, 3274 (44.4%) with colorectal cancer, 703 (9.5%) with small intestine cancer, and 600 (8.1%) with appendiceal cancer. The median age at diagnosis was 64 (Interquartile Range (IQR), 53-75). Median follow-up was 11 months (IQR 3-22). 3709 patients (50.3%) were female. The majority was White (76.2%). 3942 (53.5%) were married. 5679 (77.0%) were insured. 4343 (58.9%) received chemotherapy and 3682 (49.9%) received surgery. Compared to PC of appendiceal cancer primary, stomach cancer primary had an increased risk of CSM (HR = 4.89; 95% CI 4.23-5.65), followed by colorectal cancer (HR = 2.78, 95% CI 2.41-3.21), and small intestine (HR = 1.17; 95% CI 0.98-1.41). Across all patients, surgery and chemotherapy were associated with a lower risk of CSM. Conclusions: Primary tumor origin significantly affects outcomes of gastrointestinal malignancies with PC. Surgery and chemotherapy were associated with decreased CSM. [Table: see text]
Impact of consensus molecular subtyping (CMS) on survival in the CO.26 trial of durvalumab plus tremelimumab versus best supportive care (BSC) in metastatic colorectal cancer (mCRC).
Authors: Jonathan M. Loree, James T. Topham, Hagen Fritz Kennecke, Harriet Feilotter, Young S Lee, Shakeel Virk, Scott Kopetz, Dzifa Yawa Duose, Ganiraju C. Manyam, Jeffrey S Morris, Dipen M. Maru, Daniel Renouf, Derek J. Jonker, Dongsheng Tu, Christopher J. O'Callaghan, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2022)

3551 Background: CO.26 was a phase 2 trial (2-sided α=0.1 and 80% power) that randomized 180 patients with refractory mCRC 2:1 to durvalumab + tremelimumab vs BSC with improved overall survival (OS) (HR 0.73, 90%CI 0.55-0.97, P=0.07). A Nanostring assay validated for use with FFPE was used to determine CMS for correlation with outcome. Methods: Archival FFPE from 163/180 (91%) of patients (pts) underwent RNA extraction and CMS subtyping. Cox proportional hazard models evaluated the prognostic and predictive impact of CMS on overall survival. Results: CMS distribution was skewed towards CMS4 (76%), with lower prevalence of CMS1 (2%), CMS2 (16%) and CMS3 (2%). There were 7/163 cases of indeterminate CMS (4%). Subgroup analysis was restricted to CMS2 and CMS4 based on sample size. With BSC alone, CMS2 showed trends to worse OS compared to all other patients pooled (HR 1.93, 90% CI 1.03-3.61, P=0.085), while CMS4 did not (HR 0.86, 90% CI 0.50-1.48, P=0.64). OS but not progression free survival (PFS) was improved with durvalumab + tremelimumab in the overall population. OS was improved with durvalumab + tremelimumab among patients with CMS2 tumors (HR 0.39, 90% CI 0.19-0.82, P=0.035) but not in patients with CMS4 tumors (HR 0.73, 90% CI 0.52-1.02, P=0.12) compared to BSC. Neither CMS2 (P-interaction=0.37) nor CMS4 (P-interaction=0.91) were predictive of OS benefit from durvalumab + tremelimumab compared to BSC. Disease control rate (DCR) trended to being better among CMS4 (24/85) than CMS2 cancers (1/15, OR 5.51, 90% CI 1.10-29.88, P=0.11) or CMS4 vs all non CMS4 cancers (1/21, OR 7.87, 90% CI 1.65-41.98, P=0.023) for patients on durvalumab + tremelimumab. PFS was not improved with durvalumab + tremelimumab in CMS2 (P=0.19) or CMS4 (P=0.29) cancers relative to BSC. Conclusions: In this trial of refractory colorectal cancer, we saw a shift in CMS subtype with more CMS4 than expected. Compared to CMS4, CMS2 showed stronger signals towards improved OS with durvalumab + tremelimumab but had a lower disease control rate. Differences in immune signaling by CMS may be important determinants of which component of immune regulation needs to be targeted in mCRC to improve outcomes. Clinical trial information: NCT02870920. [Table: see text]
Modulatory effect of kilohertz frequency alternating current neuromodulation of the pudendal nerves on the anal canal and anal sphincter in the rat
Authors: R.L. Coolen, K.M. Emmer, P.I. Spantidea, E. Van Asselt, J.R. Scheepe, W.A. Serdijn, B.F.M. Blok
Journal: European Urology (2022)
Eosinophilic gastrointestinal diseases make a name for themselves: A new consensus statement with updated nomenclature
Authors: Benjamin L. Wright, Justin T. Schwartz, Melanie A. Ruffner, Glenn T. Furuta, Nirmala Gonsalves, Evan S. Dellon, Seema S. Aceves
Journal: Journal of Allergy and Clinical Immunology (2022)